Researchers investigating a known gene risk factor for Alzheimer's disease discovered it is associated with lower levels of beta amyloid—a brain protein involved in Alzheimer's—in cognitively healthy older people.

The findings suggest that a mechanism other than one related to beta amyloid accumulation may influence disease risk associated with the gene. The study, by researchers at the National Institute on Aging (NIA) at the National Institutes of Health (NIH), was published online September 27, 2012, in the journal Biological Psychiatry.

The scientists studied a variation in the complement receptor-1 (CR1) gene, a newly identified gene associated with risk for late-onset Alzheimer's disease, in cognitively normal older volunteers. Participants with this gene variant were found to have less brain amyloid than those without the risk variant. In addition, the CR1 gene variant was found to interact with APOE, the most robust genetic risk factor for Alzheimer's disease, to influence the amount of brain amyloid.

"The prevailing hypothesis has implicated factors increasing beta amyloid in the brain as an integral element of Alzheimer's disease pathology," said NIA director Richard J. Hodes. "This study indicates the importance of exploring and understanding other distinct mechanisms that may be at work in this disease."

Using a brain scan called Pittsburgh Compound B positron emission tomography (PiB PET), the researchers measured brain amyloid in 57 cognitively normal older people with an average age of 78.5 in the Baltimore Longitudinal Study of Aging (BLSA). The researchers also looked at PiB PET data from 22 cognitively normal people about the same average age in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Of the 57 BLSA participants, 17 carried the Alzheimer's risk variant of the CR1 gene, while four of the 22 ADNI participants carried the variant.

"We found that brain amyloid burden in the group with the CR1 risk variant was lower than in the group without it. This difference in brain amyloid between the two groups is statistically significant in several brain regions," said lead author Madhav Thambisetty, , chief of the clinical and translational neuroscience unit in the Laboratory of Behavioral Neuroscience in NIA's intramural research program. "That suggests to us that the CR1 risk factor gene, if it contributes to Alzheimer's disease, does it in a way unrelated to increasing amyloid burden.”

"The findings suggest that the increased risk of Alzheimer's associated with CR1 is not driven by an increase in amyloid in the brain and that we may also need to consider multiple genetic risk factors in combination," Thambisetty continued. "It may be possible that CR1 acts through other mechanisms, distinct from those that increase amyloid deposition in the brain. These may include influencing inflammation in the brain, but further research is needed to identify what these other mechanisms might be.”